Heterocyclic substituted pyrazinoylguanidines

ABSTRACT

The case involves novel heterocyclic substituted pyrazinoylguanidines and a process for preparing same. The heterocyclic pyrazinoylguanidines are eukalemic agents possessing diuretic and natriuretic properties.

SUMMARY OF THE INVENTION

The instant case covers novel heterocyclic substitutedpyrazinoylguanidine compounds and a process for making the same. Thenovel pyrazinecarboxamides of this invention are depicted in Formula Ibelow. ##STR1## wherein R¹ is hydrogen or lower alkyl having from 1 to 5carbon atoms such as methyl, ethyl, isopropyl, n-butyl, n-pentyl,

R² is hydrogen, lower alkyl having from 1 to 5 carbon atoms such asmethyl, ethyl, isopropyl and n-pentyl,

R³ is a 5 or 6 membered heterocyclic ring containing from 1 to 3heterocyclic atoms selected from the elements N, O or S, said ringcontaining from 0 to 2 substituents selected from lower alkyl having 1to 5 carbon atoms, halo, oxy or hydroxy.

X is halogen such as chloro, bromo, fluoro or iodo,

and the pharmaceutically acceptable non-toxic acid addition saltsthereof.

The preferred compounds of this invention, in other words, those havingenhanced diuretic, saluretic activity while maintaining unchangedpotassium blood levels are those compounds of Formula I wherein

R¹ is hydrogen,

R² is hydrogen, or lower alkyl having from 1 to 3 carbon atoms butparticularly isopropyl,

R³ is as previously defined; X is chloro and the pharmaceuticallyacceptable non-toxic acid addition salts thereof.

Particular definitions of R³ can be ##STR2##

Specifically preferred compounds of this invention are as follows:

3,5-diamino-6-chloro-N-[(2-thiazolinylamino)aminomethylene]-2-pyrazinecarboxamide;

3,5-diamino-N-[(2-thiazolylamino)aminomethylene]-6-chloro-2-pyrazinecarboxamide;

3-amino-6-chloro-5-isopropylamino-N-[(2-thiazolinylamino)aminomethylene]-2-pyrazinecarboxamide;

3,5-diamino-6-chloro-N-[(2-oxazolinylamino)aminomethylene]-2-pyrazinecarboxamide;

3,5-diamino-6-chloro-N-{[2-(4,5-dihydro)thiazinylamino]aminomethylene}-2-pyrazinecarboxamidehydrochloride hemihydrate.

The compounds of this invention as shown by Formula I and the preferredcompounds discussed above are useful because they possess diuretic andnatriuretic properties. In addition, they are useful eukalemicsaluretics, in other words, the compounds of the instant case causeneither loss or abnormal retention of potassium ions. Other well knowndiuretics such as furosemide, chlorthalidone and acetazolamide cause anincrease in potassium excretion which often results in muscularweakness. Thus, the compounds of this invention maintain the excretionof potassium at approximately normal levels while causing an increasedrenal elimination of sodium ions and water which is the desirablecharacteristic of the diuretic.

Also covered within the scope of the above Formula I compounds and thepreferred compounds are the pharmaceutically acceptable acid additionsalts thereof. These salts can be made by reacting the free base with apharmaceutically acceptable acid such as for example, hydrochloric acid,sulfuric acid, hydrobromic acid or isethionic acid. These salts, asstated above, are to be considered as included in this invention.

The products of this invention can be administered to patients (bothhuman and animal) in the form of pills, tablets, capsules, elixirs,injectable preparations and the like. They can be administered eitherorally or parentally or any other feasible method as known to thoseskilled in the art such as intravenously or in the form of suppositoriesand the like.

The type of formulation to be administered can be comprised of one ormore of the compounds of this invention as the only essential activeingredient of the pharmaceutical formulation. The formulations aremerely combinations of the active ingredient mentioned withpharmaceutically inert carriers and the like. Several pharmaceuticalformulations are prepared as shown in Example 27.

The compounds of this invention are advantageously administered at adosage range of from about 5 mg. to about one gram per day or a somewhathigher or lower dosage at the physician's discretion, preferably insubdivided amounts on a 2 to 4 times a day regimen and most preferablyat a dosage range from 10 to 500 mg. per day. It will be realized bythose skilled in the art that the dosage range for any particularpatient (animal or human) will depend upon the severity of the diseasetreated, weight of the patient and any other condition which thephysician or other person skilled in the art will take account of.

The compounds disclosed in this invention in Formula I and the preferredcompounds can be formed according to either of the two processesdescribed herein. The first process can be depicted by the followingequation: ##STR3## involving a reaction of a pseudothiourea compound IIwith a substituted amine III to produce the desired product.

A pseudothiourea (Compound II) is reacted with an amine (III) to yieldthe desired compounds of Formula I. This reaction is preferably carriedout in an inert solvent such as, for example, tetrahydrofuran,1,2-dimethoxyethane or bis(2-methoxyethyl)ether if the amine compoundIII is a solid or without solvent if the amine compound III is a liquid.The reaction is best carried out in a mole ratio of 1 to 4 moles of theamine Compound III to one mole of the pseudothiourea Compound II. Thereaction is preferably carried out at a temperature of from 25° C. tothe reflux temperature of the particular solvent used. It is alsocarried out for a time of 1 to 48 hours. The latter conditions oftemperature and time, however, are not critical to the reaction and canbe adjusted by those skilled in the art. The product which can beisolated from the reaction mixture by methods known in the art generallyby, for example, adding crushed ice to the reaction mixture toprecipitate the desired compounds I. Detailed descriptions of thisprocess are contained in the Examples. One can prepare thepseudothiourea compounds according to the following reaction schemewhich starts with the known pyrazinoate IV. ##STR4##

In the preparation of the pseudothiourea Compound II, one can begin byreacting the pyrazinoate IV with cyanamide and sodium methoxide to yieldan intermediate cyanamide compound, V, which is then reacted withhydrogen sulfide to yield a thiourea compound VI. This thiourea CompoundVI is then reacted with methyl iodide to yield the desiredpseudothiourea starting material II. As stated previously Compound IV isknown in the art, such as for example from U.S. Pat. Nos. 3,313,813 and4,087,526.

A second reaction for forming the end product starts by reacting apyrazinoic acid VII with carbonyl diimidazole to form an activeacylating agent VIII (not isolated) which intermediate is then reactedwith a substituted guanidine IX to yield the desired product. This isdepicted in the following equation: ##STR5##

In this process a pyrazinoic acid VII is reacted withcarbonyldiimidazole to yield an active acylating agent VIII which is notisolated. This portion of the reaction is carried out in an organicsolvent such as dimethylformamide at about 10° C. to 40° and for a timeof 1 to 8 hours. The reaction mixture is then treated with an aqueoussolution of the substituted guanidine IX at a temperature of about 25°C. to 100° C. for a time of from 1 to 48 hours. The desired product I isthen isolated from the reaction mixture by known methods such as byadding water to precipitate the product I.

In both processes described above R¹, R², R³ and X are as defined forthe compounds of Formula I.

All the starting materials used in the two processes described above areshown in and disclosed in U.S. Pat. No. 3,313,813 mentioned previouslyor at least can be obviously prepared from compounds disclosed in theaforementioned patent. The preparation of those not shown in U.S. Pat.No. 3,313,813 and which are not obviously prepared therefrom is shown inthe Examples.

EXAMPLE 11-(3-Amino-5-isopropylamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide Step A:(2-Amino-5-isopropylamino-6-chloropyrazinoyl)cyanamide

To a solution of sodium methoxide (19.0 g., 0.35 mole) in methanol (300ml.) is added cyanamide (15 g., 0.36 mole) and methyl3-amino-5-isopropylamino-6-chloropyrazinoate (29 g., 0.118 mole). Thereaction mixture is refluxed overnight, evaporated at reduced pressureto 1/2 volume, added to ice (100 g.) and neutralized with acetic acid togive (2-amino-5-isopropylamino-6-chloropyrazinoyl)cyanamide which meltsat 232° C. with decomposition after recrystallization from isopropanol.

Elemental analysis for C₉ H₁₁ ClN₆ O: Calc: C, 42.44; H, 4.35; N, 3300;Found: C, 42.52; H, 4.36; N, 33.25.

Step B: (3-Amino-5-isopropylamino-6-chloropyrazinoyl)thiourea

To a stirred solution of(3-amino-5-isopropylamino-6-chloropyrazinoyl)cyanamide (6.0 g., 0.0235mole) in pyridine (40 ml) is added triethylamine (4 ml.). The reactionmixture is heated on a steam bath for 11/2 hours while a slow stream ofhydrogen sulfide gas is bubbled into the solution. The reaction mixtureis cooled and added to ice-water to give 6 g. of(3-amino-5-isopropylamino-6-chloropyrazinoyl)thiourea which melts at195° C. after recrystallization from ethanol.

Elemental analysis for C₉ H₁₃ ClN₆ OS: Calc.: C, 37.43; H, 4.54; N,29.11; Found: C, 37.45; H, 4.54; N, 29.31.

Step C:1-(3-Amino-5-isopropylamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide

A solution of (3-amino-5-isopropylamino-6-chloropyrazinoyl)thiourea (6.0g.) and methyl iodide (15 ml) in acetone (60 ml.) is refluxed for 11/2hours and cooled in an ice bath to give 8.7 g. of1-(3-amino-5-isopropylamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide which melts at 185° C.

EXAMPLE 21-(3-Amino-5-dimethylamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide

A solution of (3-amino-5-dimethylamino-6-chloropyrazinoyl)thiourea (2.0g.) and methyl iodide (5 ml.) in acetone (60 ml.) is heated at refluxfor 1/2 hour during which time the1-(3-amino-5-dimethylamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide precipitates, m.p. 195° C.

Elemental analysis for C₉ H₁₃ ClN₆ OS.HI Calc.: C, 25.94; H, 3.39; N,20.17; Found: C, 26.13; H, 3.31; N, 20.50.

EXAMPLE 3 1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide

A solution of (3,5-diamino-6-chloropyrazinoyl)thiourea (1.0 g.) andmethyl iodide (4 ml.) in acetone (100 ml.) is heated at reflux for onehour during which time the1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodideprecipitates m.p. 222° C. with decomposition.

Elemental analysis for C₇ H₉ ClN₆ OS.HI; Calc.: C, 21.63; H, 2.59; N,21.63; Found: C, 21.97; H, 2.68; N, 21.50.

EXAMPLE 4 Preparation of3,5-Diamino-6-chloro-N-[(3-pyridylamino)aminomethylene]-2-pyrazinecarboxamidehemihydrate

1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide(970 mg., 0.0025 mole) is added to a solution of 3-aminopyridine (940mg., 0.01 mole) in dry tetrahydrofuran (20 ml.) and the mixture isheated at reflux for 2 hours, then added to crushed ice-water (200 ml.)to precipitate 423 mg. of3,5-diamino-6-chloro-N-[(3-pyridylamino)aminomethylene]2-pyrazinecarboxamidehemihydrate, m.p. 220°-2° C.

Elemental analysis for C₁₁ H₁₁ ClN₈ O.1/2H₂ O: Calc.: C, 41.85; H, 3.83;N, 35.49; Cl, 11.23; Found: C, 41.37; H, 3.91; N, 35.58; Cl, 11.58.

    __________________________________________________________________________                  Substituted                                                     Ex.                                                                              Pseudothiourea                                                                           Amine    Solvent  End Product and Analysis                      __________________________________________________________________________    5  1-(3,5-diamino-6-                                                                        3-amino-1,2,4-                                                                         Tetrahydrofuran                                                                        3,5-diamino-6-chloro-N-[3-[1,2,4-                chloropyrazinoyl)-                                                                       triazole (250 ml.)                                                                              triazolyl]amino)aminomethylene]-                 2-methyl-2-thio-                                                                         (8.4 g.,          2-pyrazinecarboxamide hemihydrate                pseudourea . HI                                                                          0.1 mole)         (2.75 g.)                                        (9.7 g.,                     Melting point: >300° C.                   0.025 mole)                  C.sub.8 H.sub.9 ClN.sub.10 O . 1/2                                            H.sub.2 O:                                                                    Calc.: C, 31.43; H, 3.30;                                                       Cl, 11.60;                                                                  Found: C, 31.68; H, 3.07;                                                       Cl, 11.94.                                  6  1-(3,5-diamino-6-                                                                        3-aminopyrazole                                                                        tetrahydrofuran                                                                        3,5-diamino-N-[(3-pyrazolylamino)-               chloropyrazinoyl)-                                                                       (3.32 g.,                                                                              (50 ml.) aminomethylene]-6-chloro-2-                      2-methyl-2-thio-                                                                         0.04 mole)        pyrazinecarboxamide hemihydrate                  pseudourea . HI              (2.62 g.) Melting point: 224° C.          (3.88 g.,                    C.sub.9 H.sub.10 ClN.sub.9 O . 1/2                                            H.sub.2 O                                        0.01 mole)                   Calc.: C, 35.48; H, 3.64; N, 41.37;                                           Found: C, 35.32; H, 3.52; N, 41.32            7  1-(3,5-diamino-6-                                                                        2-amino-4-methyl                                                                       tetrahydrofuran                                                                        3,5-diamino-N-[ 2-(4-methyl)-                    chloropyrazinol)-                                                                        thiazole (100 ml.)                                                                              thiazolylamino]aminomethylene-                   2-methyl-2-thio-                                                                         (3.42 g.,         6-chloro-2-pyrazinecarbox-                       pseudourea . HI                                                                          0.03 mole)        amide (1.0 g.)                                   3.88 g.,                     Melting point: 258- 60° C.                0.01 mole)                   C.sub.10 H.sub.11 ClN.sub.8 OS:                                               Calc: C, 36.76; H, 3.39; N, 34.29;                                            Found: C, 36.76; H, 3.28, N, 34.28.           8  1-(3,5-diamino-6-                                                                        2-amino-2-                                                                             bis(2-methoxy-                                                                         3,5-diamino-6-chloro-N-[(2-                      chloropyrazinoyl)-                                                                       thiazoline                                                                             ethyl)ether                                                                            thiazolinylamino)aminomethyl-                    2-methyl-2-thio-                                                                         (6.12 g.,                                                                              (100 ml.)                                                                              ene]-2-pyrazinecarboxamide                       pseudourea . HI                                                                          0.06 mole)        (1.56 g.) Melting point: 241-3°                                        C.                                               (5.82 g.,                    C.sub.9 H.sub.11 ClN.sub.8 OS:                   0.015 mole)                  Calc.: C, 34.34; H, 3.52;                                                       N, 35.60;                                                                   Found: C, 34.34; H, 3.43;                                                       N, 35.12.                                   9  1-(3,5-diamino-6-                                                                        2-amino- tetrahydrofuran                                                                        3,5-diamino-N-[(2-thiazolylamino)-               chloropyrazinoyl)-                                                                       thiazole (100 ml.)                                                                              aminomethylene]-6-                               2-methyl-2-thio                                                                          (4.00 g.,         chloro-2-pyrazinecarboxamide                     pseudourea . HI                                                                          0.04 mole)        (1.12 g.)                                        (3.58 g.,                    Melting point: 229-31° C.                 0.01 mole)                   C.sub.9 H.sub.9 ClN.sub.8 OS:                                                 Calc.: C, 34.57; H, 2.90;                                                       N, 35.83;                                                                   Found: C, 34.10; H, 2.85;                                                       N, 35.66                                    10 1-(3,5-diamino-6-                                                                        4-amino-1,2,4-                                                                         bis(2-methoxy-                                                                         3,5-diamino-N-[(1,2,4-triazol-                   chloropyrazinoyl)-                                                                       triazole ethyl)ether                                                                            4-ylamino)aminomethylene]-                       2-methyl-2-thio-                                                                         (1.68 g.,                                                                              (25 ml.) 6-chloro-2-pyrazinecarbox-                       pseudourea . HI                                                                          0.02 mole)        amide hemihydrate (920 mg.)                      (1.94 g.,                    Melting point: 275-7° C.                  0.005 mole)                  C.sub.8 H.sub.9 ClN.sub.10 O . 1/2                                            H.sub.2 O:                                                                    Calc.: C, 31.43; H, 3.30;                                                       N, 45.82;                                                                   Found; C, 31.60; H, 2.90;                                                       N, 45.38.                                   11 1-(3,5-diamino-6-                                                                        2-amino- none     3,5-diamino-N-[(2-pyridylamino)-                 chloropyrazinoyl)-                                                                       pyridine          aminomethylene]-6-chloro-2-                      2-methyl-2-thio                                                                          (4.70 g.,         pyrazinecarboxamide . 1/2 H.sub.2 O              pseudourea . HI                                                                          0.05 mole)        (350 mg.)                                        (1.94 g.,                    Melting point: 218-220° C.                0.005 mole)                  C.sub.11 H.sub.11 ClN.sub.8 O . 1/4                                           H.sub.2 O:                                                                    Calc.: C. 42.45; H, 3.72;                                                       N, 36.01; Cl, 11.39;                                                        Found: C, 42.40; H, 3.58;                                                       N, 35.86; Cl, 11.61.                        12 1-(3,5-diamino-6-                                                                        N-aminopiperidine                                                                      none     3,5-diamino-N-[(piperidin-1-yl-                  chloropyrazinoyl)-                                                                       (10 ml.)          amino)aminomethylene]-6-chloro-                  2-methyl-2-thio-             2-pyrazinecarboxamide (1.45 g)                   pseudourea . HI              Melting point: 137-9° C.                  (3.88 g.,                    C.sub.11 H.sub.17 ClN.sub.8 O:                   0.01 mole)                   Calc.: C, 43.17; H, 6.19;                                                       N, 32.48;                                                                   Found: C, 42.96; H, 6.23;                                                       N, 32.49                                    13 1-(3-amino-6-                                                                            2-aminothiazoline                                                                      bis(2-methoxy-                                                                         3-amino-6-chloro-5-di-                           chloro-5-dimethyl-                                                                       (2.04 g.,                                                                              ethyl)ether                                                                            methylamino-N-[(2-thia-                          aminopyrazinoyl)-                                                                        0.02 mole)                                                                             (20 ml.) zolinylmino)aminomethyl-                         2-methyl-2-thio              ene]-2-pyrazinecarbox-                           pseudourea . HI              amide (340 mg.)                                  (2.2 g.,                     Melting point: 221-4° C.                  0.0053 mole)                 C.sub.11 H.sub.15 ClN.sub.8 OS:                                               Calc.: C, 38.54; H, 4.41;                                                       N, 32.69;                                                                   Found: C, 38.88; H, 4.44;                                                       N, 32.82.                                   14 1-(3-amino-6-chloro-                                                                     2-amino- bis(2-methoxy-                                                                         3-amino-6-chloro-5-isopropyl-                    5-isopropylamino-                                                                        thiazoline                                                                             ethyl)ether                                                                            amino-N-[(2-thiazolinylamino)-                   pyrazinoyl)-2-methyl-                                                                    (3.06 g.,                                                                              (50 ml.) aminomethylene]-2-pyrazine-                      2-thiopseudourea                                                                         0.03 mole)        carboxamide (650 mg.)                            hydroiodide                  Melting point: 210-12° C.                 (4.3 g., 0.01 mole)          C.sub.12 H.sub.17 ClN.sub.8 OS:                                               Calc.: C, 40.39; H, 4.81;                                                       N, 31.40; Cl, 9.94;                                                         Found: C, 40.18; H, 4.74;                                                       N, 30.84; Cl, 9.59.                         15 1-(3,5-diamino-6-                                                                        2-amino- bis(2-methoxy-                                                                         3,5-diamino-6-chloro-N-                          chloropyrazinoyl)-                                                                       oxazoline                                                                              ethyl)ether                                                                            [(2-oxazolinylamino)amino-                       2-methyl-2-thio-             methylene]-2-pyrazinecarbox-                     pseudourea . HI              amide                                                                         Melting point: 199-200° C.                                             C.sub.9 H.sub.11 ClN.sub.8 O.sub.2 :                                          Calc.: C, 36.19; H, 3.71;                                                       N, 37.51;                                                                   Found: C, 36.25; H, 3.65;                                                       N, 37.23.                                   __________________________________________________________________________

EXAMPLE 16 Preparation of3,5-Diamino-6-chloro-N-[(4-thiomorpholinyl)aminomethylene]-2-pyrazinecarboxamide

Thiomorpholine hydrochloride (2.10 g., 0.015 mole), triethylamine (2.1ml., 0.015 mole), and1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide(1.94 g., 0.005 mole) are heated in tetrahydrofuran (50 ml.) at refluxfor 4 hrs. The reaction mixture is added to ice-water to precipitate 590mg. of3,5-diamino-6-chloro-N-[(4-thiomorpholinyl)aminomethylene]-2-pyrazinecarboxamidewhich melts at 234°-6° C. after reprecipitation from dilute hydrochloricacid with sodium hydroxide.

Elemental analysis for C₁₀ H₁₄ ClN₇ OS: Calc.: C, 38.04; H, 4.47; N,31.05; Found: C, 37.91; H, 4.46; N, 31.21.

Following the procedure of Example 16 but substituting the followingamounts of major reactants in place of the corresponding reactants ofExample 16, there is obtained the appropriate listed end product.

    __________________________________________________________________________                 Substituted                                                      Ex.                                                                              Pseudothiourea                                                                          Amine   Solvent   End Product and Analysis                       __________________________________________________________________________    17 1-(3,5-diamino-6-                                                                       2-amino-1,3,4-                                                                        bis(2-meth-                                                                         Et.sub.3 N                                                                        3,5-diamino-N-{[2-(1,3,4-                         chloropyrazinoyl)-                                                                      thiadiazole                                                                           oxyethyl)-                                                                          (4.2                                                                              thiadiazolyl)amino]amino-                         2-methyl-2-thio-                                                                        hydrochloride                                                                         ether ml, methylene}-6-chloro-                              pseudourea . HI                                                                         (4.14 g.,                                                                             (50 ml.)                                                                            0.03                                                                              2-pyrazinecarboxamide                             (3.88 g., 0.03 mole)    mole)                                                                             (510 mg.)                                         0.01 mole)                  Melting point: 297° C.                                                 C.sub.8 H.sub.8 ClN.sub.9 OS:                                                 Calc.: C, 31.33; H, 2.84;                                                       N, 39.40;                                                                   Found C, 31.34; H, 2.72;                                                        N, 39.24.                                    18 1-(3,5-diamino-6-                                                                       N-aminopyrrol-                                                                        tetrahydro                                                                          Et.sub.3 N                                                                        3,5-diamino-6-chloro-N-                           chloropyrazinoyl)-                                                                      idine hydro-                                                                          furan (4.2                                                                              [(pyrrolidin-1-ylamino)-                          2-methyl-2-thio-                                                                        chloride                                                                              (100 ml.)                                                                           ml, aminomethylene]-2-pyrazine-                       pseudourea . HI                                                                         (2.61 g.,     0.03                                                                              carboxamide (960 mg)                              (3.38 g., 0.03 mole)    mole)                                                                             Melting point: 106-9° C.                   0.01 mole)                  C.sub.10 H.sub.15 ClN.sub.8 O:                                                Calc.: C, 40.21; H, 5.06;                                                       N, 37.51;                                                                   Found: C, 40.58; H, 5.12;                                                       N, 37.08                                     __________________________________________________________________________

EXAMPLE 19 Preparation of3,5-Diamino-6-chloro-N-[(1,1-dioxotetrahydrothien-3-ylamino)aminomethylene]-2-pyrazinecarboxamidemonohydrate

3-Amino-1,1-dioxotetrahydrothiophene hydrochloride (17.1 g., 0.1 mole)is added to a solution of sodium methoxide (5.4 g., 0.1 mole) inmethanol (150 ml.) with stirring at 25° C. After 0.5 hr. the sodiumchloride is filtered off and the filtrate concentrated to drynessleaving the free amine residue which is suspended in tetrahydrofuran(250 ml.). 1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudoureahydroiodide (9.7 g., 0.025 mole) is added and the mixture heated atreflux for 2 hrs., the product filtered then dissolved in hot water andtreated with 10 N sodium hydroxide solution to precipitate 5.33 g. of3,5-diamino-6-chloro-N-[(1,1-dioxotetrahydrothien-3-ylamino)aminomethylene]-2-pyrazinecarboxamidemonohydrate. m.p. 193°-5° C.

Elemental analysis for C₁₀ H₁₄ ClN₇ O₃ S.H₂ O: Calc.: C, 32.84; H, 4.41;N, 26.80; Found: C, 33.26; H, 4.09; N, 27.03.

Following the procedure of Example 19 but substituting the followingamounts of major reactants in place of the corresponding reactants ofExample 19 there is obtained the appropriate listed end product.

    __________________________________________________________________________                  Substituted                                                     Ex.                                                                              Pseudothiourea                                                                           Amine    NaOCH.sub.3                                                                         End Product and Analysis                         __________________________________________________________________________    20 1-(3,5-diamino-6-                                                                        4-piperidone                                                                           (1.08 g.,                                                                           3,5-diamino-6-chloro-N-[(4-oxo-                     chloropyrazinoyl)-                                                                       monohydrate                                                                            0.02 mole)                                                                          piperidinyl)aminomethylene]-2-                      2-methyl-2-thio-                                                                         hydrochloride  pyrazinecarboxamide hemihydrate                     pseudourea . HI                                                                          (3.07 g.,      (380 mg.)                                           (1.94 g.,  0.02 mole)     Melting point: 244-7° C.                     0.005 mole)               C.sub.11 H.sub.14 ClN.sub.7 O.sub.2 . 1/2                                     H.sub.2 O:                                                                    Calc.: C, 41.19; H, 4.71;                                                       N, 30.57; Cl, 11.05;                                                        Found: C, 40.58; H, 4.39;                                                       N, 30.69; Cl, 11.43.                           21 1-(3,5-diamino-6-                                                                        2-amino-4,5-di-                                                                        (1.62 g.,                                                                           3,5-diamino-N-{[2-(4,5-dimethyl)-                   chloropyrazinoyl)-                                                                       methylthiazole                                                                         0.03 mole)                                                                          thiazoylamino]aminomethylene}-                      2-methyl-2-thio-                                                                         hydrobromide   6-chloro-2-pyrazinecarboxamide                      pseudourea . HI                                                                          (6.27 g.,      (1.92 g.)                                           (3.88 g.,  0.03 mole)     Melting point: 264-6° C.                     0.01 mole)                C.sub.11 H.sub.13 ClN.sub.8 OS:                                               Calc.: C, 38.77; H, 3.85;                                                       N, 32.88;                                                                   Found: C, 38.68; H, 3.85;                                                       N, 32.99                                       22 1-(3,5-diamino-6-                                                                        2-amino-5,6-di-                                                                        (1.62 g.,                                                                           3,5-diamino-6-chloro-N-{[2-(4,5-                    chloropyrazinoyl)-                                                                       hydro-4H-1,3-                                                                          0.03 mole)                                                                          dihydro)thiozinylamino]amino-                       2-methyl-2-thio-                                                                         thiazine hydro-                                                                              methylene}-2-pyrazinecarbox-                        pseudourea . HI                                                                          chloride (4.59 g.,                                                                           amide hydrochloride hemihydrate                     (3.88 g.,  0.03 mole)     (271 g.) Melting point: 253-4° C.            0.01 mole)                C.sub.10 H.sub.13 ClN.sub.8 OS . HCl . 1/2                                    H.sub.2 O;                                                                    Calc.: C, 32.09; H, 4.04;                                                       N, 29.94;                                                                   Found: C, 32.00; H, 3.99;                                                       N, 30.27.                                      __________________________________________________________________________

EXAMPLE 23 Preparation of3,5-Diamino-6-chloro-N-{[3-(2-oxooxazolidinyl)amino]aminomethylene}-2-pyrazinecarboxamide

1-(3,5-Diamino-6-chloropyrazinoyl)-2-methyl-2-thiopseudourea hydroiodide(2.23 g., 0.005 mole) is added to a solution of 3-amino-2-oxazolidinone(2.04 g., 0.02 mole) in dry methanol (100 ml.) with stirring at 25° C.under N₂. After 20 hours the solid precipitate is removed, dissolved inH₂ O, then treated with 15 N ammonium hydroxide to give 950 mg. of3,5-diamino-6-chloro-N-{[3-(2-oxooxazolidinyl)amino]aminomethylene}-2-pyrazine═carboxamide,m.p. 281°-3° C.

Elemental analysis for C₉ H₁₁ ClN₈ O₃ : Calc.: C, 34.35; H, 3.52; N,35.61; Found: C, 34.15; H, 3.60; N, 35.21.

EXAMPLE 243,5-Diamino-6-chloro-N-[(2-oxazolinylamino)aminomethylene]-2-pyrazinecarboxamide.3/4H₂ O

N,N'-Carbonyldiimidazole (1.62 g., 0.01 mole) is added to a solution of3,5-diamino-6-chloropyrazinoic acid (1.89 g., 0.01 mole) in drydimethylformamide (80 ml) at 25° C. under N₂. After 1 hour the1-(3,5-diamino-6-chloro-2-pyrazinoyl)imidazole formed is not isolatedbut is treated in situ with 2-guanidinooxazoline sulfate (3.54 g., 0.02mole) dissolved in H₂ O (15 ml.) -10 N NaOH solution (2 ml.). Afterstirring at 55° C. for 20 hours, removing the insoluble solid,azetroping most of the DMF with p-xylene, then adding the residue to H₂O, there is obtained 460 mg. of3,5-diamino-6-chloro-N-[(2-oxazolinylamino)aminomethylene]-2-pyrazinecarboxamide.3/4H₂ O which melts at 199°-200° C. after reprecipitation from dil. HClwith NH₄ OH.

Elemental analysis for C₉ H₁₁ ClN₈ O₂ : Calc.: C, 36.19; H, 3.71; N,37.51; Found: C, 36.25; H, 3.65; N, 37.23.

EXAMPLE 253,5-Diamino-6-chloro-N-[(2-imidazolylamino)aminomethylene]-2-pyrazinecarboxamide

N,N'-Carbonyldiimidazole (1.62 g., 0.01 mole) is added to a solution of3,5-diamino-6-chloropyrazinoic acid (1.89 g., 0.01 mole) in drydimethylformamide (80 ml.) at 25° C. under N₂. After 1 hour the1-(3,5-diamino-6-chloro-2-pyrazinoyl)imidazole formed is not isolated,but is treated in situ with 2-guanidinoimidazole dihydrochloride (3.96g., 0.02 mole) dissolved in H₂ O (15 ml.) -10 N NaOH solution (2 ml.).After stirring at 55° C. for 20 hours, removing the insoluble solid,azetroping most of the DMF with p-xylene, then adding the residue to H₂O, there is obtained3,5-diamino-6-chloro-N-[(2-imidazolylamino)aminomethylene]-2-pyrazinecarboxamide.

EXAMPLE 263,5-Diamino-6-chloro-N-[(2-imidazolinylamino)aminomethylene]-2-pyrazinecarboxamide

N,N'-Carbonyldiimidazole (1.62 g., 0.01 mole) is added to a solution of3,5-diamino-6-chloropyrazinoic acid (1.89 g., 0.01 mole) in drydimethylformamide (80 ml.) at 25° C. under N₂. After 1 hour the1-(3,5-diamino-6-chloro-2-pyrazinoyl)imidazole formed is not isolated,but is treated in situ with 2-guanidinoimidazoline (2.54 g., 0.02 mole)dissolved in H₂ O (15 ml.) -10 N NaOH solution (2 ml.). After stirringat 55° C. for 20 hours, removing the insoluble solid, azetroping most ofthe DMF with p-xylene, then adding the residue to H₂ O, there isobtained3,5-diamino-6-chloro-N-[(2-imidazolinylamino)aminomethylene]-2-pyrazinecarboxamide.

EXAMPLE 27

Compressed Tablet containing 50 mg. of active ingredient.

    ______________________________________                                                              Per tablet, Mg.                                         ______________________________________                                        3,5-diamino-6-chloro-N-[(2-                                                   thiazolinylamino)aminomethyl-                                                 ene]-2-pyrazinecarboxamide                                                                            50                                                    Calcium phosphate dibasic                                                                             200                                                   Ethyl cellulose (as 5% solution in ethanol)                                                           5                                                     Unmixed granulation     255                                                   Add:                                                                          Starch, corn            14                                                    Magnesium stearate      1                                                                             270                                                   ______________________________________                                    

Directions

Mix the active ingredient above and calcium phosphate and reduce to aNo. 60 mesh powder. Granulate with Ethocel in alcohol and pass the wetgranulation through a No. 10 screen. Dry the granulation at 110° F. for12-18 hours. Dry grind to a No. 20 mesh. Incorporate the "adds" andcompress into tablets each weighing 270 mg.

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R¹ ishydrogen, lower alkyl having from 1 to 5 carbon atoms;R² is hydrogen,lower alkyl having 1 to 5 carbon atoms; R³ is a 5 or 6 memberedheterocyclic ring containing from 1 to 3 heterocyclic atoms selectedfrom the elements N, O or S, said ring containing from 0 to 2substituents selected from lower alkyl having 1 to 5 carbon atoms, halo,oxy or hydroxy; X is halo, andthe pharmaceutically acceptable non-toxicacid addition salts thereof.
 2. A compound of the formula: ##STR7##wherein R¹ is hydrogen;R² is hydrogen or lower alkyl having from 1 to 3carbon atoms; R³ is a 5 or 6 membered heterocyclic ring containing from1 to 3 heterocyclic atoms selected from the elements N, O or S, saidring containing from 0 to 2 substituents selected from lower alkylhaving 1 to 5 carbon atoms, halo, oxy or hydroxyand the pharmaceuticallyacceptable non-toxic acid addition salts thereof.
 3. A compound of claim1 wherein R³ is ##STR8##
 4. A compound of claim 2 whereinR¹ is hydrogen;R² is hydrogen; R³ is ##STR9## to yield3,5-diamino-6-chloro-N-[(2-thiazolinylamino)aminomethylene]-2-pyrazinecarboxamide.5. A compound of claim 2 whereinR¹ is hydrogen; R² is isopropyl; R³ is##STR10## to yield3-amino-6-chloro-5-isopropylamino-N-[(2-thiazolinylamino)aminomethylene]-2-pyrazinecarboxamide.6. A compound of claim 2 whereinR¹ is hydrogen; R² is hydrogen; R³ is##STR11## to yield3,5-diamino-6-chloro-N-[(2-oxazolinylamino)aminomethylene]-2-pyrazinecarboxamide.7. A compound of claim 2 whereinR¹ is hydrogen; R² is hydrogen; R³ is##STR12## to yield3,5-diamino-N-[(2-thiazolylamino)aminomethylene]-6-chloro-2-pyrazinecarboxamide.8. A compound of claim 2 whereinR¹ is hydrogen; R² is hydrogen; R³ is##STR13## to yield3,5-diamino-6-chloro-N-{[2-(4,5-dihydro)thiazinylamino]aminomethylene}-2-pyrazinecarboxamidehydrochloride hemihydrate.